Non-Hodgkin Lymphoma (NHL) incidence and mortality have been rapidly increasing over the past 50 years, and these trends are largely unexplained. Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world, and appears to be biologically related to small lymphocytic NHL. Some of the highest incidence and mortality rates in the world occur in the upper midwestern United States. In this study, we propose to systematically test hypotheses regarding medical history, pesticide/farming exposures, diet and early life factors that have been raised by recent research as being important in the etiology of NHL or CLL. We will also test novel hypotheses that genes with functional, common variant polymorphisms involved in immune function and regulation are associated with risk of NHL or CLL; these include genes encoding inflammatory and regulatory cytokines (IL-1A, IL-1B, IL-1RN, TNFalpha, Thl/Th2 cytokines (LTA, INFgamma, IL-4, IL- 4RA, IL-6, IL-IO, IL-13), and chemokines (IL-8, SDF-1, CCR2, CCR5). We will also evaluate the extent that measured environmental factors might modify or confound any observed association between these candidate genes and risk of NHL and CLL. Furthermore, in secondary analyses, we will evaluate gene-gene (within and between pathways), as well as selected gene-environment interactions. We will also begin to address the issue of etiologic heterogeneity for the most common subtypes of NHL. To test these hypotheses, we propose a clinic-based case-control study. We will enroll incident cases of NHL (N=914) and CLL (N=238) diagnosed at the Mayo Clinic over a 4.7-year time period who are residents of Minnesota, Iowa or Wisconsin at the time of diagnosis. All cases will be reviewed by a single hematopathologist and classified into the WHO classification system, and frozen and paraffin tissue will be banked. Cases will be compared to 1,152 clinic-based controls frequency matched on age, sex, and county of residence. Participants will complete structured self-administered questionnaires and provide a blood sample for DNA and serum. There is generally excellent statistical power to test the a priori hypotheses of interest. We have assembled an interdisciplinary research team for this study, and this study will create an outstanding research resource. In summary, we will evaluate critical hypotheses regarding environmental and genetic risk factors for NHL and CLL, and should greatly contribute to our understanding the causes and possible prevention of these cancers.